Fragile X syndrome is one of the most commonly inherited forms of mental retardation and is caused by the loss of FMR1 gene function. Patients with fragile X syndrome suffer from a variety of symptoms including; mental retardation, attention deficit, hyperactivity, sleep disorders, anxiety, unstable mood and autistic-like behaviors. In previous studies, we have characterized a Drosophila model for Fragile X, based on dfmr1 loss of function mutations. Surprisingly, dfmr1 mutants display several phenotypes that bear similarity to Fragile X symptoms. These phenotypes include courtship defects, memory deficits, lack of proper circadian regulation and neuroanatomical defects. Recent observations have indicated that enhanced metabotropic glutamate receptor (mGluR) signaling is a cause of a large number of the Fragile X symptoms. In support of this model, we previously demonstrated that treatment with mGluR antagonists rescues several of the dfmr1 mutant phenotypes, including the courtship defects, memory and some neuroanatomical defects. We now are poised to examine the biological relevance of a reported deficit in cAMP regulation. We will also map the requirements of dfmr1 in the brain for normal circadian behavior. In another study we have been investigating the mechanism by which dFMR1 functions with a key member of the small RNA pathways to regulate circadian behavior. These studies will impact our basic understanding of the primary defects that lead to fragile X, as well a improve our general knowledge of the processes of cognition and circadian behavior. PUBLIC HEALTH RELEVANCE: This proposal investigates a Drosophila model for Fragile X Syndrome at multiple levels, including examination of defects in physiology and neuronal circuits that cause relevant phenotypes in memory and circadian behavior. Findings from this research will both increase our understanding of the underlying defects that cause fragile X as well as increase our basic knowledge on the requirements for proper cognition and circadian behavior, as well as how the small RNA pathway is linked to the FMR1.